Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 10459–10467 | Cite as

FOXR2 contributes to cell proliferation and malignancy in human hepatocellular carcinoma

Original Article

Abstract

Forkhead box R2 (FOXR2), a member of forkhead box (FOX) family, has been identified as an oncogene in medulloblastoma and breast cancer recently. However, the expression and function of FOXR2 in hepatocellular carcinoma cell (HCC) are still unclear. Here, we report that FOXR2 is frequently upregulated in 25/42 (59.5 %) of HCC specimens compared with neighboring non-cancerous tissues in messenger RNA (mRNA) level and further confirmed by immunohistochemistry analysis in protein level. Cellular function analyses revealed that FOXR2 promoted cell growth and colony formation, whereas knockdown of FOXR2 by RNA inference inhibited cell growth and decreased the growth ability of HCC cells in soft agar. Moreover, we also found FOXR2 overexpression facilitated the development of tumor xenografts in nude mice model. In addition, we validated β-catenin, Skp2, c-Myc, and Gli-1 as the potential downstream effectors of FOXR2 in the regulation of cell proliferation and malignancy by quantitative real-time PCR analysis. Collectively, our data suggest that FOXR2 promotes cell proliferation and malignancy in HCC and could be a novel promising therapeutic target for this disease.

Keywords

Hepatocellular carcinoma FOXR2 Cell proliferation Malignancy 

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81302064), Shanghai Natural Science Foundation of China (13ZR1434000), Specialized Research Fund for the Doctoral Program of Higher Education (20130072120060), and Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2014-04).

Compliance with ethical standards

Sample tissues were obtained from HCC patients by way of surgery and with informed consent in Shanghai East Hospital. The use of human samples and all animal handling and experimental procedures were approved by the Ethics Committee of the Shanghai East Hospital.

Conflicts of interest

None.

References

  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995–2004.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.CrossRefPubMedGoogle Scholar
  4. 4.
    Jackson BC, Carpenter C, Nebert DW, Vasiliou V. Update of human and mouse forkhead box (FOX) gene families. Hum Genomics. 2010;4:345–52.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 2009;10:233–40.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013;328:198–206.CrossRefPubMedGoogle Scholar
  7. 7.
    Kuda M, Kohashi K, Yamada Y, Maekawa A, Kinoshita Y, Nakatsura T, Iwamoto Y, Taguchi T, Oda Y. FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutic target. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2015Google Scholar
  8. 8.
    Halasi M, Gartel AL. FOX(M1) news—it is cancer. Mol Cancer Ther. 2013;12:245–54.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yan JH, Zhao CL, Ding LB, Zhou X. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer. Biochem Biophys Res Commun. 2015;466:111–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Weiss MB, Abel EV, Dadpey N, Aplin AE. FOXD3 modulates migration through direct transcriptional repression of TWIST1 in melanoma. Mol Cancer Res: MCR. 2014;12:1314–23.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Li D, Mei H, Qi M, Yang D, Zhao X, Xiang X, et al. FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget. 2013;4:2021–44.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tian HP, Lun SM, Huang HJ, He R, Kong PZ, Wang QS, et al. DNA methylation affects the SP1-regulated transcription of FOXF2 in breast cancer cells. J Biol Chem. 2015;290:19173–83.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Song H, He W, Huang X, Zhang H, Huang T. High expression of FOXR2 in breast cancer correlates with poor prognosis. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2015.Google Scholar
  14. 14.
    Koso H, Tsuhako A, Lyons E, Ward JM, Rust AG, Adams DJ, et al. Identification of FoxR2 as an oncogene in medulloblastoma. Cancer Res. 2014;74:2351–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Rahrmann EP, Watson AL, Keng VW, Choi K, Moriarity BS, Beckmann DA, et al. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet. 2013;45:756–66.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, et al. Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res. 2009;69:3501–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhang X, Hao J. Development of anticancer agents targeting the Wnt/beta-catenin signaling. Am J Cancer Res. 2015;5:2344–60.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Song X, Xin N, Wang W, Zhao C. Wnt/beta-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis. Oncotarget. 2015;6:35579–88.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Hao Z, Huang S. E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. Front Biosci (Landmark ed). 2015;20:474–90.CrossRefGoogle Scholar
  20. 20.
    Ott G. Impact of MYC on malignant behavior. Hematol / Educ Program Am Soc Hematol Am Soc Hematol Educ Program. 2014;2014:100–6.Google Scholar
  21. 21.
    Chen XL, Cao LQ, She MR, Wang Q, Huang XH, Fu XH. Gli-1 siRNA induced apoptosis in Huh7 cells. World J Gastroenterol. 2008;14:582–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Oncology and Hematology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
  2. 2.Department of Oncology, East HospitalDalian Medical UniversityShanghaiChina
  3. 3.Research Center for Translational Medicine, Shanghai East HospitalTongji University School of MedicineShanghaiChina

Personalised recommendations